X chromosome inactivation (XCI) achieves dosage balance in mammals by repressing one of two X chromosomes in females. X-linked diseases occur in females when a defective gene is present on the active X chromosome (Xa). In some cases, a normal, wild type copy of the gene is present on the inactive X chromosome (Xi), and the severity of the disease may depend on the prevalence (skewing) of inactivation of the X chromosome carrying the wild type gene. Reactivating the entire Xi is undesirable as cancers could arise as a result of X-chromosome gene overdosing (Yildirim et al., 2013, Cell 152: 727-742). Locus-specific reactivation of the non-disease silent allele on the Xi would be therapeutic in many cases of X-linked disease, such as Rett Syndrome.